US20150299345A1 - Antibacterial monomers, antibacterial resins and dental composites comprising the antibacterial resins - Google Patents

Antibacterial monomers, antibacterial resins and dental composites comprising the antibacterial resins Download PDF

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US20150299345A1
US20150299345A1 US14/436,377 US201314436377A US2015299345A1 US 20150299345 A1 US20150299345 A1 US 20150299345A1 US 201314436377 A US201314436377 A US 201314436377A US 2015299345 A1 US2015299345 A1 US 2015299345A1
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antibacterial
methacrylate
dimethylamino
filler
resin
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Huakun Xu
Michael Weir
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University of Maryland at Baltimore
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University of Maryland at Baltimore
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F20/00—Homopolymers and copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride, ester, amide, imide or nitrile thereof
    • C08F20/02—Monocarboxylic acids having less than ten carbon atoms, Derivatives thereof
    • C08F20/10—Esters
    • C08F20/34—Esters containing nitrogen, e.g. N,N-dimethylaminoethyl (meth)acrylate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K6/00—Preparations for dentistry
    • A61K6/15—Compositions characterised by their physical properties
    • A61K6/17—Particle size
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K6/00—Preparations for dentistry
    • A61K6/60—Preparations for dentistry comprising organic or organo-metallic additives
    • A61K6/69—Medicaments
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K6/00—Preparations for dentistry
    • A61K6/80—Preparations for artificial teeth, for filling teeth or for capping teeth
    • A61K6/884—Preparations for artificial teeth, for filling teeth or for capping teeth comprising natural or synthetic resins
    • A61K6/887—Compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • A61K6/889—Polycarboxylate cements; Glass ionomer cements
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/0241—Containing particulates characterized by their shape and/or structure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A61K8/24—Phosphorous; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A61K8/26—Aluminium; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/81—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions involving only carbon-to-carbon unsaturated bonds
    • A61K8/8141—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides or nitriles thereof; Compositions of derivatives of such polymers
    • A61K8/8152—Homopolymers or copolymers of esters, e.g. (meth)acrylic acid esters; Compositions of derivatives of such polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/005—Antimicrobial preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/41—Particular ingredients further characterized by their size
    • A61K2800/413—Nanosized, i.e. having sizes below 100 nm
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/54—Polymers characterized by specific structures/properties
    • A61K2800/542—Polymers characterized by specific structures/properties characterized by the charge
    • A61K2800/5426—Polymers characterized by specific structures/properties characterized by the charge cationic

Definitions

  • Tooth caries are the result of a dietary carbohydrate-modified bacterial infectious disease, one of the most common bacterial infections in humans (Loesche, 1986; van Houte, 1994; Featherstone, 2000).
  • the basic mechanism of dental caries is demineralization, or mineral loss, through attack by acid generated by bacteria (Featherstone, 2004; Deng, 2004; Totiam et al., 2007). Therefore, acidogenic bacteria growth and biofilm formation are responsible for dental caries (Loesche, 1986; van Houte, 1994; Zero, 1995; Featherstone, 2000; Deng et al., 2005; Cenci et al., 2009).
  • Plaque formation has been described to have three steps: pellicle formation, bacteria colonization, and biofilm maturation (Burne, 1998).
  • pellicle forms on the tooth surface with adsorbed components from saliva, mucosa, and bacteria (Carlen et al., 2001). Bacteria then adhere and colonize on this surface to grow into a biofilm, which is a heterogeneous structure consisting of clusters of various types of bacteria embedded in an extracellular matrix (Stoodley et al., 2008).
  • Cariogenic bacteria such as Streptococcus mutans ( S. mutans ) and lactobacilli in the plaque can take nutrients from carbohydrates and produce organic acids. Acid production causes demineralization to the tooth structure beneath the biofilm.
  • Resin composites have been increasingly used for tooth cavity restorations because of their aesthetics, direct-filling capability, and enhanced performance (Ferracane, 1995; Bayne et al., 1998; Lim et al., 2002; Ruddell et al., 2002; Watts et al., 2003; Drummond, 2008).
  • the present invention is directed to new antibacterial monomers that differ based on the alkyl chain length.
  • the monomers include the following:
  • DMAPM dimethylamino propyl methacrylate
  • DMAHM dimethylamino hexyl methacrylate
  • DMAHPM dimethylamino heptyl methacrylate
  • DMANM dimethylamino nonyl methacrylate
  • DMADM dimethylamino decyl methacrylate
  • DAUDM dimethylamino undecyl methacrylate
  • DADDM dimethylamino dodecyl methacrylate
  • DMATTDM dimethylamino tetradecyl methacrylate
  • DMAPDM dimethylamino pentadecyl methacrylate
  • DMAHDM dimethylamino hexadecyl methacrylate
  • DMAHPDM dimethylamino heptadecyl methacrylate
  • DMAODM dimethylamino octadecyl methacrylate
  • DMANDM dimethylamino nonadecyl methacrylate
  • DMAIOM dimethylamino icosyl methacrylate
  • DMADOM dimethylamino docosyl methacrylate
  • the present invention is directed to antibacterial resins comprising a resin and an antibacterial monomer of the present invention.
  • the resin is one or more resins selected from the group consisting of bis-GMA (bisphenol glycidyl methacrylate), TEGDMA (triethylene glycol dimethacrylate), HEMA (2-hydroxyethyl methacrylate), UDMA (urethane dimethacrylate), PMGDM (pyromellitic acid glycerol dimethacrylate), ethoxylated bisphenol A dimethacrylate (EBPADMA), methacryloyloxyethyl phthalate (MEP), methacrylate-modified polyalkenoic acid, a hydrophobic monomer, a hydrophilic monomer, a poly acid-modified polymer, a light-cured polymer, a self-cured polymer, a duel cured polymer, and a heat-cured polymer.
  • the resin is a 1:1 mass ratio of bis-GMA (bisphenol
  • the antibacterial resins may comprise one or more than one of the antibacterial monomers of the invention.
  • the combined amount of the one or more antibacterial monomers in the antibacterial resins of the present invention is a mass fraction of from about 0.5% to about 50% of the antibacterial resin.
  • the antibacterial resin comprises a combined amount of from about 1% to about 25%, about 2.5% to about 20%, about 5% to about 15%, or about 7.5% to about 12.5% by mass of one or more of the antibacterial monomers.
  • the antibacterial resin comprises a combined amount of about 2.5%, about 5%, about 7.5% or about 10% by mass of one or more of the antibacterial monomers.
  • the antibacterial resins may further comprise one or more additional antibacterial agents, including, but not limited to, quaternary ammonium salts (QAS), silver-containing nanoparticles (NAg), chlorhexidine particles, TiO2 particles and ZnO particles.
  • QAS quaternary ammonium salts
  • NAg silver-containing nanoparticles
  • chlorhexidine particles TiO2 particles
  • ZnO particles ZnO particles.
  • quaternary ammonium salts may be a mass fraction of between about 1% to 30% of the mass of the antibacterial resin, preferably about 7.5% to about 15% of the mass of the antibacterial resin.
  • silver-containing nanoparticles may be a mass fraction of between about 0.01% and about 20% of the mass of the antibacterial resin, preferably 0.08% to 10% of the mass of the antibacterial resin.
  • the present invention is directed to dental composites comprising an antibacterial resin of the present invention and a filler.
  • the filler is one or more of a glass filler, a ceramic filler, a polymer-based filler, and nanoparticles of amorphous calcium phosphate (NACP).
  • the glass filler may be barium boroaluminosilicate, strontium-alumino-fluoro-silicate glass, silicon dioxide, fluoroaluminosilicate glass, a ytterbium tri-fluoride filler, or a fiber glass filler.
  • the filler is barium boroaluminosilicate.
  • the ceramic filler may be a porcelain filler, a quartz filler, or a zirconia filler.
  • the dental composites may comprise one or more of the antibacterial resins of the present invention and one or more fillers.
  • the amount of the one or more of the antibacterial resins in the dental composite is between about 1% to about 70% of the mass of the composite.
  • the antibacterial resin is a mass fraction of from about 10% to about 45%, about 20% to about 40%, or about 25% to about 35% of the dental composite.
  • the antibacterial resin is a mass fraction of about 10%, about 15%, about 20%, about 25%, about 30%, or about 35% of the dental composite.
  • the amount of the one or more fillers in the dental composite is between about 5% to about 90% of the mass of the composite.
  • the filler is a mass fraction of from about 10% to about 85%, about 20% to about 85%, or about 30% to about 80% of the dental composite.
  • the filler is a mass fraction of about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, or about 50% of the composite.
  • NACP When NACP is present as a filler, whether alone or in combination with one or more other fillers, it may make up between about 1% and 80% of the mass of the composite.
  • the NACP is a mass fraction of from about 5% to about 60%, about 10% to about 40%, about 15% to about 35%, or about 20% to about 30% of the composite.
  • the NACP is a mass fraction of about 25%, about 25.5%, about 26%, about 26.5%, about 27%, about 27.5%, about 28%, about 28.5%, about 29%, about 29.5% or about 30% of the composite.
  • the NACP particles may range in size from about 10 nm to about 500 nm. In certain aspects, the NACP particles range in size from about 50 nm to about 300 nm, about 50 nm to about 200 nm, or about 75 nm to about 200 nm.
  • the filler is two different fillers, for example, a glass filler and NACP, or a ceramic filler and NACP.
  • the total amount of the two fillers in the dental composite will again be about 5% to about 90% of the mass of the composite.
  • the first filler e.g., a glass filler
  • the second filler e.g., NACP
  • the first filler e.g., a glass filler
  • the first filler e.g., a glass filler
  • NACP e.g., NACP
  • the first filler e.g., a glass filler
  • the second filler e.g., NACP
  • the first filler e.g., a glass filler
  • the second filler e.g., NACP
  • the present invention is directed to a dental composite comprising about 50% glass filler, about 20% NACP and about 30% antibacterial resin by mass of the composite, wherein the antibacterial resin comprises about 2.5% by mass DMADDM, DMAPDM, or DMAHDM as the antibacterial monomer.
  • the present invention is directed to a dental composite comprising about 50% glass filler, about 20% NACP and about 30% antibacterial resin by mass of the composite, wherein the antibacterial resin comprises about 5% by mass DMADDM, DMAPDM, or DMAHDM as the antibacterial monomer.
  • the present invention is directed to a dental composite comprising about 50% glass filler, about 20% NACP and about 30% antibacterial resin by mass of the composite, wherein the antibacterial resin comprises about 7.5% by mass DMADDM, DMAPDM, or DMAHDM as the antibacterial monomer.
  • the present invention is directed to a dental composite comprising about 50% glass filler, about 20% NACP and about 30% antibacterial resin by mass of the composite, wherein the antibacterial resin comprises about 10% by mass DMADDM, DMAPDM, or DMAHDM as the antibacterial monomer.
  • the glass filler is barium boroaluminosilicate
  • the resin is a 1:1 mass ratio of bis-GMA and TEGDMA
  • the NACP particles range in size from about 50 nm to about 200 nm.
  • the new antibacterial monomer with a chain length of 12 (DMADDM) had the highest fibroblast viability (p ⁇ 0.05).
  • DMADDM and MDPB are less cytotoxic, with higher cell viability, than BisGMA, a monomer commonly used in dental resins.
  • FIG. 2 A modified Titankin reaction was used to synthesize new antibacterial monomers: (A) DMAHM, and (B) DMADDM.
  • DMAH N,N-dimethylaminohexane.
  • BEMA 2-bromoethyl methacrylate.
  • DMAHM dimethylaminohexane methacrylate.
  • DMAD 1-(dimethylamino)docecane.
  • DMADDM dimethylaminododecyl methacrylate.
  • EtOH anhydrous ethanol. The number of the alkyl chain length units was 6 for DMAHM and 12 for DMADDM.
  • FIGS. 3 A-B FTIR spectra of reactants and products for: (A) DMAHM, and (B) DMADDM.
  • NACP+ODMADDM refers to NACP nanocomposite containing 0% DMADDM;
  • NACP+0.75DMADDM refers to NACP nanocomposite containing 0.75% of DMADDM; and so on. Adding up to 3% of DMADDM into NACP nanocomposite resulted in no significant decrease in strength and elastic modulus. Horizontal line indicates values that are not significantly different from each other (p>0.1).
  • FIGS. 5 A-E Typical confocal laser scanning microscopy (CLSM) images of live/dead stained biofilms on composites. Live bacteria were stained green, and dead bacteria were stained red. Live/dead bacteria that were close to, or on the top of, each other produced yellow/orange colors. Composite control and NACP nanocomposite had primarily live bacteria. The DMADDM-containing nanocomposites showed substantial antibacterial activity.
  • CLSM confocal laser scanning microscopy
  • NACP+ODMADDM refers to NACP nanocomposite containing 0% DMADDM;
  • NACP+0.75DMADDM refers to NACP nanocomposite containing 0.75% of DMADDM; and so on. In each plot, values with dissimilar letters are significantly different (p ⁇ 0.05).
  • NACP+ODMADDM refers to NACP nanocomposite containing 0% DMADDM;
  • NACP+0.75DMADDM refers to NACP nanocomposite containing 0.75% of DMADDM; and so on.
  • values with dissimilar letters are significantly different (p ⁇ 0.05). Note the log scale for the y-axis.
  • the monomers include the following: dimethylamino propyl methacrylate (DMAPM), dimethylamino hexyl methacrylate (DMAHM), dimethylamino heptyl methacrylate (DMAHPM), dimethylamino octyl methacrylate (DMAOM), dimethylamino nonyl methacrylate (DMANM), dimethylamino decyl methacrylate (DMADM), dimethylamino undecyl methacrylate (DMAUDM), dimethylamino dodecyl methacrylate (DMADDM), dimethylamino tridecyl methacrylate (DMATDM), dimethylamino tetradecyl methacrylate (DMATTDM), dimethylamino pentadecyl methacrylate (DMAPDM), dimethylamino hexadecyl methacrylate
  • the antibacterial resins of the present invention comprise any resin (or combination of resins) that is suitable for dental use in a subject, such as a human, and one or more of the antibacterial monomers.
  • the novel antibacterial monomers that are used in the preparation of the antibacterial resins greatly increase the ability of the resins to resist bacterial colonization and biofilm formation.
  • Suitable resins will be those resins commonly used in dental applications.
  • Such resins typically comprise a matrix that is of a hardenable dental polymer.
  • Exemplary resins include bis-GMA (bisphenol glycidyl methacrylate), TEGDMA (triethylene glycol dimethacrylate), HEMA (2-hydroxyethyl methacrylate), UDMA (urethane dimethacrylate), PMGDM (pyromellitic acid glycerol dimethacrylate), ethoxylated bisphenol A dimethacrylate (EBPADMA), methacryloyloxyethyl phthalate (MEP), methacrylate-modified polyalkenoic acid, a hydrophobic monomer, a hydrophilic monomer, a poly acid-modified polymer, a light-cured polymer, a self-cured polymer, a duel cured polymer and a heat-cured polymer, as well combinations of two or more of these polymers.
  • a suitable combination is Bis-GMA and TEGDMA at 1:1 mass ratio.
  • the resins used in the antibacterial resins of the invention may be rendered light-curable through the addition of appropriate compounds to the resin.
  • camphorquinone and ethyl 4-N,N-dimethylaminobenzoate may be added to a resin comprising Bis-GMA and TEGDMA thereby rendering the resin light-curable.
  • about 0.2% camphorquinone and about 0.8% ethyl 4-N,N-dimethylaminobenzoate may be added to a resin comprising Bis-GMA and TEGDMA in about a 1:1 mass ratio to render the resin light-curable.
  • the amount of the one or more antibacterial monomers present in the antibacterial resins of the present invention is a combined amount of antibacterial monomer of from about 0.5% to about 50% by mass of the antibacterial resin.
  • the antibacterial resin comprises a combined amount of from about 1% to about 25%, from about 2.5% to about 25%, from about 2.5% to about 20%, from about 2.5% to about 15%, from about 5% to about 25%, from about 5% to about 20%, from about 5% to about 15%, from about 7.5% to about 25%, from about 7.5% to about 20%, about 7.5% to about 15% or from about 7.5% to about 12.5% of the mass of the antibacterial resin.
  • the amount of the one or more antibacterial monomers present in the antibacterial resin is a combined amount of about 1, 2, 2.5, 3, 4, 5, 6, 7, 7.5, 8, 9, 10, 11, 12, 12.5, 13, 14, 15, 16, 17, 17.5, 18, 19, 20, 21, 22, 22.5, 23, 24, 25, 26, 27, 27.5, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 or 50% of the mass of the antibacterial resin.
  • the antibacterial resins of the present invention may further comprise one or more additional antibacterial agents, including, but not limited to quaternary ammonium salts (QAS), silver-containing nanoparticles (NAg), chlorhexidine particles, TiO2 particles and ZnO particles.
  • additional antibacterial agents including, but not limited to quaternary ammonium salts (QAS), silver-containing nanoparticles (NAg), chlorhexidine particles, TiO2 particles and ZnO particles.
  • Suitable QASs include both polymerizable monomers and non-polymerizable small molecules, and include, but are not limited to, bis(2-methacryloyloxy-ethyl) dimethyl-ammonium bromide (QADM), methacryloyloxydodecylpyridinium bromide, methacryloxylethyl benzyl dimethyl ammonium chloride, methacryloxylethyl m-chloro benzyl dimethyl ammonium chloride, methacryloxylethyl cetyl dimethyl ammonium chloride, cetylpyridinium chloride, and methacryloxylethyl cetyl ammonium chloride, QAS chlorides, QAS bromides, QAS monomethacrylates, QAS dimethacrylates, and pre-fabricated QAS particles.
  • QADM bis(2-methacryloyloxy-ethyl) dimethyl-ammonium bromide
  • QADM bis(2-methacryloy
  • Suitable silver-containing nanoparticles include, but are not limited to, silver 2-ethylhexanoate salt, silver-containing glass particles and silver benzoate. In addition to silver salts, pre-formed silver nanoparticles can be used.
  • the QAS may make up between about 1% and about 30% of a mass fraction of the antibacterial resin. In certain aspects, the QAS will make up between about 2% and about 25%, about 5% and about 20%, or about 7.5% and about 15% of a mass fraction of the antibacterial resin, or about 1%, 2.5%, 5%, 7.5%, 10%, 12.5, 15%, 17.5%, 20%, 22.5%, 25%, 27.5% or 30% of a mass fraction of the antibacterial resin.
  • NAg may make up between about 0.01% and about 20% of a mass fraction of the antibacterial resin. In certain aspects, NAg will make up between about 0.05% and about 5%, or 0.08% and about 10%, of a mass fraction of the antibacterial resin, or about 0.01%, 0.08%, 0.15%, 0.20%, 0.25%, 0.30%, 0.35%, 0.40%, 0.45%, 0.50%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5% or 5.0% of a mass fraction of the antibacterial resin. In one aspect, NAg makes up about 0.08% of a mass fraction of the antibacterial resin.
  • the silver particle size can range from about 1 nm to about 1000 nm, and in one aspect, from about 2 nm to about 500 nm.
  • the dental composites of the present invention comprise an antibacterial resin of the present invention and a filler.
  • the antibacterial resins used in the dental composites may be any of the antibacterial resins described herein, or a combination of the antibacterial resins of the present invention.
  • the amount of antibacterial resin present in the dental composites of the present invention may also vary, but the antibacterial resin will generally comprise about 1% to about 70% of the mass of the composite.
  • the antibacterial resin will comprise about 1% to about 45%, about 1% to about 40%, about 1% to about 35%, about 1% to about 30%, about 1% to about 25%, about 1% to about 20%, about 1% to about 15%, about 2.5% to about 45%, about 2.5% to about 40%, about 2.5% to about 35%, about 2.5% to about 30%, about 2.5% to about 25%, about 2.5% to about 20%, about 2.5% to about 15%, about 5% to about 45%, about 5% to about 40%, about 5% to about 35%, about 5% to about 30%, about 5% to about 25%, about 5% to about 20%, about 5% to about 15%, about 7.5% to about 45%, about 7.5% to about 40%, about 7.5% to about 35%, about 7.5% to about 30%, about 7.5% to about 25%, about 7.5% to about 20%, about 7.5% to about 15%, about 10% to about 45%, about 10% to about 40%, about 10% to about 35%, about 10% to about 30%, about 10% to about 25%, about 10% to about 20%, about 10% to about 15%,
  • the antibacterial resin is a mass fraction of from about 10%, about 15%, about 20%, about 25%, about 30%, or about 35% of the dental composite.
  • the antibacterial resin will comprise about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69 or 70% of the mass of the composite.
  • Suitable fillers include glass fillers, ceramic fillers, polymer-based fillers and NACP, or any combination thereof.
  • suitable glass fillers include barium boroaluminosilicate, strontium-alumino-fluoro-silicate glass, silicon dioxide, fluoroaluminosilicate glass, a ytterbium tri-fluoride filler, and a fiber glass filler.
  • suitable ceramic fillers include any dental ceramic such as a porcelain filler, a quartz filler, and a zirconia filler.
  • Polymer-based filler includes dental polymer that is pre-polymerized and then ground into filler particles, and polymer fibers.
  • NACP comprises nanometer-sized amorphous calcium phosphate (Ca 3 [PO 4 ] 2 ) particles that can be used to produce photo-cured nanocomposites with high Ca and PO 4 release, improved mechanical properties, and improved antibacterial properties.
  • the dental composites that include NACP exhibit greatly increased ion release at acidic, cariogenic pH, when these ions are most needed to inhibit caries.
  • the amount of filler present in the dental composites of the present invention may vary, but the filler will generally comprise about 5% to about 90% of the mass of the composite.
  • the filler will comprise about 10% to about 85%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 80%, about 20% to about 70%, about 20% to about 60%, about 20% to about 50%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, about 40% to about 80%, about 40% to about 70%, about 40% to about 60%, about 50% to about 80%, about 50% to about 70%, or about 45% to about 55% of the mass of the composite.
  • the filler is a mass fraction of about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, or about 50% of the composite.
  • the filler comprises about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83 84 or 85% of the mass of the composite.
  • the amount of NACP included as a filler may vary, but the NACP will generally comprise about 1% to about 80% of the mass of the composite.
  • the NACP will comprise about 5% to about 70%, about 5% to about 60%, about 5% to about 50%, about 5% to about 40%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 15% to about 70%, about 15% to about 60%, about 15% to about 50%, about 15% to about 40%, about 20% to about 90%, about 85% to about 70%, about 20% to about 80%, about 20% to about 70%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 25% to about 70%, about 25% to about 60%, about 25% to about 50%, about 25% to about 40%, about 30% to about 90%, about 30% to about 85%, about 30% to about 80%, about 30% to about 75%, about 30% to about 70%, about 30% to about 60%, about 15% to about 45%, about 15% to about 3
  • the NACP is a mass fraction of about 25%, about 25.5%, about 26%, about 26.5%, about 27%, about 27.5%, about 28%, about 28.5%, about 29%, about 29.5% or about 30% of the composite.
  • the NACP will comprise about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89 or 90% of the mass of the composite.
  • the size of the particles of the filler will depend on the identity of the filler or fillers.
  • the median particle diameter may be between about 0.1 and about 10 or between about 1.0 ⁇ m and about 5 ⁇ m.
  • the median particle diameter of the fillers used in the composites of the present invention may, in one aspect where barium boroaluminosilicate glass particles is the filler or one of fillers, be between about 0.1 and about 10 or between about 1.0 ⁇ m and about 5 ⁇ m.
  • NACP When NACP is included as a filler, it will vary in size, but at least about 50, 55, 60, 65, 70, 75, 80, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% of the particles, or all of the particles (100%), have an average diameter of between about 10 nm and about 500 nm. In certain aspects, the average diameter will be between about 25 nm and about 400 nm, about 50 nm and about 300 nm, about 75 nm and about 200 nm, or about 100 nm and about 150 nm. In a particular aspect, the NACP particles have an average diameter of between about 50 nm and about 200 nm.
  • the dental composite comprises:
  • the dental composite comprises:
  • the dental composite comprises:
  • the dental composites described herein can be used in a method of inhibiting growth of aciduric bacteria on a surface of a tooth of a subject, comprising restoring a surface of the tooth from which a decayed portion has been removed by applying a dental composite as described herein to the surface of the tooth, thereby inhibiting growth of aciduric bacteria on the tooth of the subject.
  • the dental composites described herein can also be used in a method of inhibiting further decay of a decaying tooth in a subject, comprising restoring a surface of the tooth from which a decayed portion has been removed by applying a dental composite as described herein to the surface of the tooth, thereby inhibiting further decay of the decaying tooth in the subject.
  • HGF Human gingival fibroblasts
  • FM fibroblast medium
  • Each unpolymerized monomer was dissolved in FM, at concentrations of: 0 (control), 0.5, 1, 2, 5, 10, 20, 40, 60, and 100 ⁇ g/mL (Huang L et al. 2011; Chai Z et al. 2011).
  • HGF were seeded in 96-well plates at 5,000 cells per well. After 2 d, 20 ⁇ L of MTT solution was added (Chai Z et al. 2011). After 4 h, the unreacted dye was removed and 150 ⁇ L, of dimethyl sulfoxide was added. Absorbance was measured via the microplate reader at 492 nm.
  • One or more antibacterial monomers with various chain lengths can be incorporated into the composite, at antibacterial resin mass fractions ranging from 1% to 50% of the composite, preferably 2% to 20% of the composite.
  • Other techniques for producing the dental composites are disclosed in WO 2012/003290, incorporated herein by reference in its entirety.
  • a modified Strutkin reaction approach was used to synthesize the new QAMs.
  • This method uses a tertiary amine group to react with an organo-halide, as described in previous studies (Antonucci J M et al. 2012; Cheng L et al. 2012a).
  • a benefit of this reaction is that the reaction products are generated at virtually quantitative amounts and require minimal purification (Antonucci J M et al. 2012).
  • 2-bromoethyl methacrylate (BEMA) was the organo halide.
  • N,N-dimethylaminohexane (DMAH) and 1-(dimethylamino) docecane (DMAD) were the two tertiary amines.
  • DMAHM dimethylaminohexane methacrylate
  • the scheme of synthesis of dimethylaminododecyl methacrylate is shown in FIG. 2B .
  • DMAD Tokyo Chemical Industry
  • BEMA BEMA
  • 3 g of ethanol A magnetic stir bar was added, and the vial was capped and stirred at 70° C. for 24 h. After the reaction was complete, the solvent was removed via evaporation. The number of the alkyl chain length units was 6 for DMAHM and 12 for DMADDM ( FIG. 2 ).
  • FTIR Fourier transform infrared spectroscopy
  • Nicolet 6700 Thermo Scientific, Waltham, Mass.
  • FTIR spectra of the starting materials and the viscous products were collected between two KBr windows in the 4000 cm ⁇ 1 to 400 cm ⁇ 1 region with 128 scans at 4 cm ⁇ 1 resolution (Antonucci J M et al. 2012). Water and CO 2 bands were removed from all spectra by subtraction.
  • 1 H NMR spectra (GSX 270, JEOL, Peabody, Mass.) of the starting materials and products were taken in deuterated chloroform at a concentration of approximately 3%. All spectra were run at room temperature, 15 Hz sample spinning, 45° tip angle for the observation pulse, and a 10 s recycle delay, for 64 scans (Antonucci J M et al. 2012).
  • FTIR showed that the C—Br absorption bands from BEMA (575 cm ⁇ 1 , 512 cm ⁇ 1 ) in curve 1 and the (CH 3 ) 2 N ⁇ bands (2822 cm ⁇ 1 , 2771 cm ⁇ 1 ) from DMAH in curve 2 disappeared in curve 3 .
  • the appearance in curve 3 of the NR 4 + peak corresponded to the formation of the quaternary ammonium group and, hence, DMAHM was successfully synthesized.
  • FIG. 3B showed the synthesis of DMADDM from the reaction of BEMA and DMAD.
  • MIC Minimum Inhibitory Concentration
  • MCC Bactericidal Concentration
  • MIC and MBC were measured using S. mutans (ATCC 700610, UA159, American Type Culture, Manassas, Va.). S. mutans is a cariogenic, aerotolerant anaerobic bacterium and the primary causative agent of dental caries (Loesche 1986). MIC and MBC were determined via serial microdilution assays (Imazato S et al. 2006; Huang L et al. 2011). Unpolymerized DMAHM or DMADM monomer was dissolved in brain heart infusion (BHI) broth (BD, Franklin Lakes, N.J.) to give a final concentration of 200 mg/mL.
  • BHI brain heart infusion
  • the previously-synthesized QADM (Antonucci J M et al. 2012; Cheng L et al. 2012a) served as an antibacterial monomer control. After incubation at 37° C. in 5% CO 2 for 48 h, the wells were read for turbidity, referenced by the negative and positive control wells. MIC was determined as the endpoint (the well with the lowest antibacterial agent concentration) where no turbidity could be detected with respect to the controls (Huang L et al. 2011). To determine MBC, an aliquot of 50 ⁇ L from each well without turbidity was inoculated on BHI agar plates and incubated at 37° C. in 5% CO 2 for 48 h. MBC was determined as the lowest concentration of antibacterial agent that produced no colonies on the plate. The tests were performed in triplicate (Huang L et al. 2011). The MIC and MBC values of the antibacterial agents against S. mutans are listed in Table 2.
  • a lower concentration of the antibacterial agent needed to inhibit the bacteria indicates a higher antibacterial potency.
  • the new DMAHM with an alkyl chain length of 6 was more potent than the previously-synthesized QADM.
  • the new DMADDM with an alkyl chain length of 12 was much more strongly antibacterial than DMAHM.
  • the MIC and MBC of DMADDM was more than two orders of magnitude lower than those of MDAHM, and approached those of the CHX control.
  • an electrostatic precipitator AirQuality, Minneapolis, Minn.
  • This method produced NACP with a mean particle size of 116 nm, as measured in a previous study (Xu H H K et al. 2011).
  • Other techniques for producing NACP are disclosed in WO 2012/003290, incorporated herein by reference in its entirety.
  • DMADDM exhibited a much greater antibacterial potency than DMAHM and QADM
  • DMADDM was used for incorporation into the NACP nanocomposite to obtain antibacterial properties.
  • BisGMA bisphenol glycidyl dimethacrylate
  • TEGDMA triethylene glycol dimethacrylate
  • were mixed at a mass ratio 1:1, and rendered light-curable with 0.2% camphorquinone and 0.8% ethyl 4-N,N-dimethylaminobenzoate (mass fractions).
  • DMADDM was mixed with the photo-activated BisGMA-TEGDMA resin at the following DMADDM/(BisGMA-TEGDMA+DMADDM) mass fractions: 0%, 2.5%, 5%, 7.5% and 10%, yielding five groups of resin, respectively.
  • a dental barium boroaluminosilicate glass of a median particle size of 1.4 ⁇ m was silanized with 4% 3-methacryloxypropyltrimethoxysilane and 2% n-propylamine (Xu H H K et al. 2011).
  • the NACP and glass particles were mixed into each resin, at the same filler level of 70% by mass, with 20% of NACP and 50% of glass (Xu H H K et al. 2011). Because the resin mass fraction was 30% in the composite, the five DMADDM mass fractions in the composite were 0%, 0.75%, 1.5%, 2.25% and 3%, respectively.
  • Other techniques for producing the dental composites are disclosed in WO 2012/003290, incorporated herein by reference in its entirety.
  • a computer-controlled Universal Testing Machine (5500R, MTS, Cary, N.C.) was used to fracture the specimens in three-point flexure using a span of 10 mm and a crosshead speed of 1 mm/min.
  • the specimens were taken out of the water and fractured within several minutes while still being wet (Cheng L et al. 2012a).
  • the NACP nanocomposite with various DMADDM mass fractions had strengths similar to that of the commercial composite control, which was not antibacterial and had no Ca and P ion release (p>0.1).
  • the elastic moduli of DMADDM-NACP nanocomposites were also similar to those of the NACP nanocomposite without DMADDM and the composite control (p>0.1).
  • the dental plaque microcosm biofilm model used human saliva as inoculum.
  • Saliva was collected from a healthy adult donor following a previous study (Cheng L et al. 2012b).
  • the donor had natural dentition without active caries or periopathology, and without the use of antibiotics within the last 3 months.
  • the donor did not brush teeth for 24 h and abstained from food or drink intake for at least 2 h prior to donating saliva (Cheng L et al. 2012b).
  • Stimulated saliva was collected during parafilm chewing and kept on ice.
  • the saliva was diluted in sterile glycerol to a concentration of 70% saliva and 30% glycerol (Cheng L et al. 2012b), and stored at ⁇ 80° C.
  • the saliva-glycerol stock was added, with 1:50 final dilution, into the growth medium as inoculum.
  • the growth medium contained mucin (type II, porcine, gastric) at a concentration of 2.5 g/L; bacteriological peptone, 2.0 g/L; tryptone, 2.0 g/L; yeast extract, 1.0 g/L; NaCl, 0.35 g/L, KCl, 0.2 g/L; CaCl 2 , 0.2 g/L; cysteine hydrochloride, 0.1 g/L; haemin, 0.001 g/L; vitamin K 1 , 0.0002 g/L, at pH 7 (McBain A J 2009).
  • mucin type II, porcine, gastric
  • Composite disks were sterilized in ethylene oxide (Anprolene AN 74i, Andersen, Haw River, N.C.). 1.5 mL of inoculum was added to each well of 24-well plates with a composite disk, and incubated in 5% CO 2 at 37° C. for 8 h. The disks were then transferred to new 24-well plates filled with fresh medium and incubated. After 16 h, the disks were transferred to new 24-well plates with fresh medium and incubated for 24 h. This totaled 48 h of incubation, which was shown to be adequate to form dental plaque microcosm biofilms on resins (Cheng L et al. 2012b; Zhang K et al. 2012).
  • the microcosm biofilms adherent on the disks were gently washed three times with phosphate buffered saline (PBS), and then stained using the BacLight live/dead bacterial viability kit (Molecular Probes, Eugene, Oreg.) (Cheng L et al. 2012b; Zhang K et al. 2012). Live bacteria were stained with Syto 9 to produce a green fluorescence, and bacteria with compromised membranes were stained with propidium iodide to produce a red fluorescence. The stained disks were examined using a confocal laser scanning microscopy (CLSM 510, Carl Zeiss, Thornwood, N.Y.).
  • CLSM 510 Carl Zeiss, Thornwood, N.Y.
  • MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was performed according to previous studies (Antonucci J M et al. 2012; Cheng L et al. 2012a). It is a colorimetric method that measures the enzymatic reduction of MTT, a yellow tetrazole, to formazan. Briefly, disks with 48-h biofilms were rinsed with PBS and transferred to 24 well plates. Then, 1 mL of MTT dye (0.5 mg/mL MTT in PBS) was added to each well and incubated for 1 h.
  • DMSO dimethyl sulfoxide
  • the biofilms on composite control and NACP+0% DMADDM had a similar metabolic activity (p>0.1).
  • Increasing the DMADDM mass fraction significantly decreased the metabolic activity of biofilms (p ⁇ 0.05).
  • the metabolic activity was approximately 5% of that on composite control.
  • the biofilms on composite control produced the most acid, similar to that on NACP+0% DMADDM.
  • the lactic acid production monotonically decreased (p ⁇ 0.05).
  • the lactic acid production by biofilms on NACP+3% DMADDM was about 1% of that on the commercial composite control.
  • microplate reader was used to measure the absorbance at 340 nm for the collected BPW solutions.
  • Standard curves were prepared using a lactic acid standard (Supelco Analytical, Bellefonte, Pa.) (Cheng L et al. 2012a; Cheng L et al. 2012b).
  • the composite control had the highest CFU counts. All three CFU counts showed a similar decreasing trend with increasing DMADM mass fraction in NACP nanocomposite (p ⁇ 0.05). Compared to the control composite, all three CFU counts on NACP+3% DMADDM were reduced by 2-3 orders of magnitude.
  • the present study demonstrated that the antibacterial monomers, such as DMADDM, could be incorporated into the NACP nanocomposite to impart a strong antibacterial activity without compromising mechanical properties.
  • the previous QADM nanocomposite reduced the MTT metoblic activity by 2-fold, compared to the same control composite (Cheng L et al. 2012c).
  • the present study using DMADDM reduced the MTT by 20-fold.
  • the previous QADM nanocomposite reduced the lactic acid production by 2-fold (Cheng L et al. 2012c); the present study using DMADDM reduced lactic acid by 2 orders of magnitude.
  • the previous QADM nanocomposite reduced the biofilm CFU counts by 3-fold (Cheng L et al. 2012c); the present study using DMADDM reduced the biofilm CFU by 2-3 orders of magnitude. Therefore, the new DMADDM-NACP nanocomposite represents a substantial improvement over previous antibacterial dental composites.

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US11452291B2 (en) 2007-05-14 2022-09-27 The Research Foundation for the State University Induction of a physiological dispersion response in bacterial cells in a biofilm
US10519270B2 (en) 2011-10-03 2019-12-31 Hyalex Orthopaedics, Inc. Polymeric adhesive for anchoring compliant materials to another surface
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CN109536145A (zh) * 2018-12-03 2019-03-29 中国石油集团川庆钻探工程有限公司 一种水溶性压裂暂堵剂及其合成方法
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CN112062978A (zh) * 2020-08-25 2020-12-11 广州大学 一种抗菌微球及其制备方法
CN113975182A (zh) * 2021-11-17 2022-01-28 深圳市尚美尔技术研发有限公司 一种抗菌补牙材料及其制备方法
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